Patients suffering from neurodegenerative disease may find hope in regenerative medicine. Huntington disease (HD) is a rare disease involving the massive loss of striatial neurons. It is a candidate for stem cell therapy and also an interesting model. There has been background work on cell transplantation in HD and it is known, from animal studies, that grafted cells can alleviate functional deficits.
The developmental and speciation stage of the donor tissue is crucial, according to Nick Allen, Ph.D., reader in genetics at the University of Wales, Cardiff. The differentiation of human embryonic stem cells into neural cells is well established, and Dr. Allen’s group has developed a chemically defined medium that decreases the number of contaminant cells.
“We now have good protocols with defined media and drugs to control the signalling pathways.” The team is currently looking at scale-up and reproducibility, using small bioreactors, with collaborators in Paris. “These human embryonic stem cells differentiate very nicely and give functional neurons.” They are trying to manipulate the signaling pathways to give the specific cells that would be of use in HD, and assessment of grafts of such neurons has begun.
Transgenic animal models of HD are a cumbersome platform for drug discovery. There is a clear need for in vitro models. “We aim to generate disease-relevant cells for screening,” said Dr. Allen, describing work his team has done on cells derived from embryos arising from pre-implantation diagnosis IVF studies for HD.
In an EU program, the Cardiff team is looking at cells from embryos that have tested positive for HD. Currently, the transcriptome of these cells is being studied and a number of genes are being validated.
However, work with IVF-derived HD embryos is limited by availability of the cells, so Dr. Allen’s group is also looking at induced pluripotent cells derived from fibroblasts of patients with HD. The advantage of this approach is that there is a clinical history attached to the patient, which is not so in the pre-implantation diagnosis IVF cells. There are also genome-wide association studies under way in HD populations. “There are very exciting times ahead as we develop sophisticated cell models together with clinical information.”